Therapy-related myelodysplasia or acute myelogenous leukemia (t-MDS/AML) is a dreaded complication and the most common cause of non-relapse mortality in patients undergoing autologous hematopoietic cell transplantation (aHCT) for Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Previous studies indicate that t-MDS/AML results from damage to hematopoietic stem cells from genotoxic cancer treatment. However, the sequential cellular and molecular changes leading to development of t-MDS/AML are not known. We are conducting a prospective, longitudinal study of patients with HL and NHL undergoing aHCT, in order to gain insight into the pathogenesis and identify predictors of susceptibility to t-MDS/AML. Patients are being followed longitudinally from pre-aHCT to five years post-aHCT, with serial banking of peripheral blood (PB) and bone marrow (BM) samples at pre-determined time-points. The known timing and nature of genotoxic exposures for management of HL or NHL, together with banking of sequentially obtained samples, provides a unique opportunity to study sequential molecular and cellular changes In this liigh-risk population. We are exploring the hypothesis that defects in DNA repair, DNA damage response and increased proliferative demand on HSC that have already acquired DNA damage may contribute to genomic instability and emergence of a malignant clone. Studies conducted during the previous grant period have indicated a role for accelerated telomere shortening and abnormal regulation of hematopoietic stem cell proliferation in the pathogenesis of t-MDS/AML and support this hypothesis. Our previous studies have also resulted in development of methodologies to evaluate DNA repair and acquisition of chromosomal aberrations in primary hematopoietic cells. We propose to build upon our previous findings and systematically investigate the role of these mechanisms in the pathogenesis of t-MDS/AML, with an overarching goal of developing biomarkers of enhanced risk of t-MDS/AML. We aim to understand the mechanisms and significance of DNA repair defects, altered telomere regulation and acquisition of cytogenetic lesions in the pathogenesis of t- MDS/AML; and to understand the interaction of these abnormalities, therapeutic exposures and demographic variables in determining risk of t-MDS/AML. Successful completion of these studies will provide insights into the pathogenesis of t-MDS/AML and allow accurate assessment of risk factors associated with the development of t-MDS/AML. Early identification of high-risk populations may aid in modification of treatment regimens to reduce risk of this complication.